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Deletion of ENTPD3 does not impair nucleotide hydrolysis in primary somatosensory neurons or spinal cord.

Abstract

Ectonucleotidases are membrane-bound or secreted proteins that hydrolyze extracellular nucleotides.xa0 Recently, we identified three ectonucleotidases that hydrolyze extracellular adenosine 5'-monophosphate (AMP) to adenosine in primary somatosensory neurons.xa0 Currently, it is unclear which ectonucleotidases hydrolyze ATP and ADP in these neurons.xa0 Ectonucleoside triphosphate diphosphohydrolases (ENTPDs) comprise a class of enzymes that dephosphorylate extracellular ATP and ADP.xa0 Here, we found that ENTPD3 (also known as NTPDase3 or CD39L3) was located in nociceptive and non-nociceptive neurons of the dorsal root ganglion (DRG), in the dorsal horn of the spinal cord, and in free nerve endings in the skin.xa0 To determine if ENTPD3 contributes directly to ATP and ADP hydrolysis in these tissues, we generated and characterized an Entpd3 knockout mouse.xa0 This mouse lacks ENTPD3 protein in all tissues examined, including the DRG, spinal cord, skin, and bladder.xa0 However, DRG and spinal cord tissues from Entpd3 (-/-) mice showed no reduction in histochemical staining when ATP, ADP, AMP, or UTP were used as substrates.xa0 Additionally, using fast-scan cyclic voltammetry (FSCV), adenosine production was not impaired in the dorsal spinal cord of Entpd3 (-/-) mice when the substrate ADP was applied.xa0 Further, Entpd3 (-/-) mice did not differ in nociceptive behaviors when compared to wild-type mice, although Entpd3 (-/-) mice showed a modest reduction in β-alanine-mediated itch.xa0 Taken together, our data indicate that deletion of Entpd3 does not impair ATP or ADP hydrolysis in primary somatosensory neurons or in dorsal spinal cord.xa0 Moreover, our data suggest there could be multiple ectonucleotidases that act redundantly to hydrolyze nucleotides in these regions of the nervous system.